JP2009511604A - Methods for treating primary and secondary forms of glaucoma - Google Patents

Abstract

Disclosed are methods and compositions for controlling (i) primary open-angle glaucoma (POAG), (ii) other forms of glaucoma, or (iii) high intraocular pressure associated with glucocorticoid therapy. The method includes administration of an angiogenesis inhibitor by local injection into the anterior segment of the eyeball, and other IOP-lowering agents. The most preferred IOP-lowering agents are angiogenesis-inhibiting steroids, especially anecoltab acetate, and the most preferred route of administration is pre-scleral injection or implant. Part of the present invention is based on the discovery that injection of anecoltab acetate into the vicinity of the anterior sclera allows control of intraocular pressure over an extended period of one to several months. This result is thought to be because the access to the trabecular meshwork of anecoltab acetate is promoted by the pre-sclera administration route.

Description

(Background of the Invention)
This application claims priority from US Application No. 60 / 726,740 (filed October 14, 2005) and US Application No. 60 / 753,751 (filed December 23, 2005).

(Field of Invention)
The present invention provides (i) primary open-angle glaucoma, (ii) other forms of glaucoma, or (iii) high intraocular pressure associated with glucocorticoid treatment, angiogenesis inhibitors and other IOP lowering agents, The present invention relates to methods and compositions for controlling by local injection into the anterior segment of the eye, in particular by injection near the anterior sclera.

(Description of related technical fields)
“Glaucoma” is a leading cause of irreversible blindness in blacks and Hispanics in the United States, a second leading cause of blindness in whites in the United States, and a major cause of blindness throughout the world, including both developed and developing countries. It is a series of erosive eye diseases. The disease is estimated to affect 0.4% to 3.3% of all adults over the age of 40 (Leske, MC et al. (1983); Bengtsson, B. (1989). Strong, N.P. (1992)). Furthermore, the frequency of appearance of this disease increases with age, exceeding 6% at 75 years of age or older (Strong, NP, (1992)). In 2010, it is estimated that 65 million people worldwide will be affected by open-angle glaucoma and closed-angle glaucoma, which will increase to 799.6 million in 2020 (Quigley and Broman 2006). In all glaucoma, decreased intraocular pressure correlates strongly with a decrease in the rate of progression of the disease and a decrease in the rate of progression toward disability and blindness. Reduction of intraocular pressure, called “intraocular pressure (IOP)” is the only known method for effective treatment of this disease. It is known that every 1 mm Hg reduction in IOP reduces the chance of progressive damage by about 10%.

  The etiology of glaucoma remains the subject of much research in the United States and other countries. The cause of the disease is still not completely clear, but it is known that the trabecular tissue of the eyeball plays a decisive role in this disease, particularly with respect to maintaining hydrodynamics within the eyeball . Specifically, if the trabecular meshwork fails to function as it should, this dysfunction will stagnate the ability of aqueous humor away from the eyeballs, leading to an increase in IOP, which is appropriate and timely. If not treated, it leads to progressive visual loss, visual impairment, and blindness.

  Increased intraocular pressure may also occur as a result of using corticosteroids to treat inflammatory diseases. Corticosteroids, in particular glucocorticoids, have recently been used for the treatment of various inflammatory diseases. For example, in the past few years, glucocorticoids, in particular, have been used by the medical community to treat certain disorders of the back of the eye. Kenalog (R) (triamcinolone acetonide), Celestone Solospan (R) (betamethasone sodium phosphate), Depo-Medrol (R) (methylprednisolone acetate), Decadron (R) (dexamethasone sodium phosphate) Decadron L .; A. (Registered trademark) (dexamethasone acetate), and Aristocort (registered trademark) (triamcinolone diacetate). Disorders treated in this way include macular edema due to vascular occlusion and diabetic retinopathy. Triamcinolone is also administered after cataract surgery and is also administered to eyes with macular edema associated with other vitreoretinopathy.

  These pharmaceuticals are generally administered locally by periocular injection or by intravitreal injection for the treatment of inflammatory disorders. Due to the lack of effective and safe treatments, there is an increasing interest in the use of glucoruticoids, for example, for the treatment of retinal edema and age-related macular degeneration (AMD). Bausch & Lomb and Control Delivery Systems recently received FDA approval for fluorocinolone acettanide delivered via an intravitreal implant for the treatment of macular edema. Oculex Pharmaceuticals is investigating a dexamethasone implant for stubborn macular edema. In addition, ophthalmologists are experimenting with intravitreal injection of triamcinolone acetonide for the treatment of recalcitrant cystic diabetic macular edema and exudative AMD.

  It is known that administering glucocorticoids for the treatment of inflammatory disorders can also lead to increased intraocular pressure. Glucocorticoids can increase the expression of myosillin (MYOC) in the trabecular meshwork, thereby increasing myosillin protein secretion. MYOC was originally discovered as a differentially expressed gene and is mapped to the glaucoma junction site GLC1A by mutations found in glaucoma patients. MYOC is expressed in a variety of tissues including trabecular meshwork. It is believed that the increased MYOC expression brought about by administration of glucocorticoids causes trabecular meshwork congestion, which in turn leads to an increase in IOP. Many authors document that intravitreal injection of triamcinolone correlates with the frequency and duration of IOP elevation. IOP elevations appear as early as 4 days and can reach IOP close to or exceeding 60 mmHg (Non-patent Document 1). Usually, IOP elevations begin 2-3 weeks after steroid infusion (Epstein et al. 1997) and can last 6-8 months (Jonas 2003; Jonas 2004). Topical administration of an IOP-lowering agent provides some relief to the increase in IOP, but often does not lower the IOP sufficiently enough to avoid damage to ocular tissue. In addition, many patients are prescribed multiple IOP-lowering agents to deal with elevated IOP, and all of them must be self-administered by topical administration.

  While treatment of such disorders of the back of the eye with glucocorticoids is effective, one of the most common complications is the sudden increase in IOP associated with steroids. This occurs within a few days, lasts for at least 6 months, requires a drug to lower this elevated IOP, and is significant because of the continuous presence of the drug in the vitreous or in or around the eyeball Can be a visually impaired complication. The etiology of this IOP elevation is only partially understood. After administration of glucocorticoids, morphological and biochemical changes of trabecular meshwork cells are seen. Such modifications include increased cell size and reorganization of the cytoskeleton, which are thought to be due in part to the profound induction of myosillin mRNA in trabecular meshwork cells.

  Patients who have increased IOP as a result of treatment with glucocorticoids are usually prescribed many IOP-lowering drugs locally to address this side effect. In many patients, the increase in IOP due to glucocorticoid administration tends to persist despite the simultaneous dosing of multiple IOP-lowering agents usually delivered locally. Recently, IOP-lowering drugs are often unable to adequately control these steroid-induced IOP elevations. In such cases, routine filtering surgery or surgical intervention with shunting may be required. Such surgery is associated with considerable intrinsic risk, particularly for subject groups that may have multiple additional risks of filtration surgery failure and complications. In addition, there is a tendency for more people to not comply 100% with their IOP-lowering agent prescriptions, and such lack of compliance can lead to blindness.

  Treatment regimens currently available for patients presenting with elevated IOP usually include one or more eye drops or pills containing an IOP-lowering compound, once a day to several times a day, regardless of the cause. Including topical administration multiple times. In addition, pills that reduce the amount of aqueous humor produced can be given in the range of 2 to 4 times a day. About 40% of patients with early glaucoma (high intraocular pressure treatment trial; “OHTS”) and about 75% of more advanced glaucoma patients (cooperative trial of early glaucoma treatment; “CIGTS”) have one to reduce IOP sufficiently. It is estimated that more glaucoma drugs are needed.

  In glaucoma treatment, both regulatory compliance and adjunct treatment are critical issues. In addition, there are currently no intraocular pressure (IOP) lowering agents that can be routinely given at intervals exceeding 24 hours per dose. All current glaucoma treatments are given topically or orally, but when added to another IOP-lowering agent, there is no conventional reduction in IOP reduction by 25%. Furthermore, in a significant number of patients, local administration of one or more existing IOP-lowering agents cannot adequately control IOP. In order to achieve sufficient control of IOP in such patients, conventional glaucoma filtration surgery or shunts are often required. There is a strong need for improved means to control the IOP of these patients without appealing to surgery. In response to this demand, the present invention provides sufficient control of IOP in such patients by using a new route of administration, in particular by pre-scleral injection of anecoltab acetate or other angiogenesis inhibitors. Provide a means for

  Many people are unable to take eye drops (Sleath et al., 2000). Furthermore, pills have many adverse events associated with them, so that over 50% of patients cannot tolerate even short-term use. In addition, many patients do not adhere to prescribed treatment regimens for topical use of drugs. The more complicated the dosage regimen, the less likely it is to adhere to the patient's treatment (Robin and Covert, 2005). The effects of the prescribed treatment regimen and the benefits provided to the patient decrease as the patient's medication is inappropriate. Furthermore, many patients do not return to regular follow-up once they are diagnosed and prescribed medication (Nordstrom et al., 2005).

  A review of the literature examining patient compliance with treatment regimens found that eye disorders (ie glaucoma) were among the 5 conditions at the bottom of the compliance list (DiMattero 2004). Low compliance rates for patients with eye disorders are due in part to changes in treatment regimen (number of prescribed daily doses, number of prescribed drugs, route of administration, compliance assessment method, and length of compliance testing period. It is thought that it may be related to Some literature estimated that compliance with eye drops regimens was in the range of 40% to 78% (Gurwitz et al. 1998; Spooner et al. 2002; Lee et al. 2000; Patel and Spaeth 1995; Claxton et al. 2001). Whatever the cause, non-compliance results in insufficient intraocular pressure control and increased visual field defects.

  Delivers sustained efficacy to patients and achieves a reduction in IOP without the need for daily self-administration of the drug, whether by one form of glaucoma or by administration of corticosteroids, There is a need for a management regimen for the treatment of elevated intraocular pressure. There is a need for a treatment that does not require supplementation of drugs and is acceptable even for people who are absent from multiple follow-ups. The methods and compositions of the present invention meet that need.

(Reference)
For further background information, reference may be made to the following documents: Depending on the degree to which they provide exemplary experimental procedures, or other details that supplement those described herein, the content of these documents is also specifically incorporated herein by reference. Included in

非特許文献１

Non-patent document 1

Singh et al., “Early Rapid Rise in Intraocular Pressure After Intravitational Triamcinone Acetonide Injection”, American Journal of Ophthalmology, 138 (2): 138 (2): 138 (7).

(Summary of the Invention)
The present invention is for treating glaucoma or increasing intraocular pressure (IOP) by administering a glaucoma therapeutic agent to the anterior segment of the patient's eye, preferably by pre-scleral administration of a drug depot. Methods and compositions for controlling In certain embodiments, the administered drug is an IOP-lowering agent. The drug administered according to the method of the present invention is an angiogenesis inhibitor such as an anti-angiogenic cortisene.

  In a preferred embodiment, the present invention provides a method for reducing intraocular pressure in a patient having some form of glaucoma. According to the method of the present invention, a composition comprising an IOP-lowering agent is administered to a patient suffering from high intraocular pressure by pre-scleral depot administration. The IOP lowering agent may be any known agent as long as it causes a decrease in intraocular pressure. For example, carbonic anhydrase inhibitors, beta blockers, alpha agonists, serotonin agonists , Ethacrynic acid, miotics, prostaglandin analogs, and angiogenesis inhibitors. The drug is preferably an angiogenesis inhibitor, for example, an angiogenesis inhibitor cortisene.

  In another preferred embodiment, the present invention provides a method for lowering intraocular pressure in a patient having or at risk for developing intraocular pressure by intravitreal injection of glucocorticoid, or other administration I will provide a. The methods of the present invention provide a therapeutically effective amount of IOP reduction for patients who have or will receive glucocorticoids for the treatment of vitreous retinal disorders or other disorders of the back of the eye. Administering a composition comprising an agent. Typically, administration of the IOP-lowering agent occurs before, after, or concurrently with intravitreal injection of glucocorticoids.

  It is contemplated that the glucocorticoid may be any glucocorticoid used to treat retinal disorders or other disorders of the back of the eye or to treat inflammation from a surgical procedure In a preferred embodiment, the glucocorticoid is triamcinolone acetonide. In another preferred embodiment, the glucocorticoid is fluocinolone acetonide, dexamethasone, prednisolone, or rotopredonisol.

  In general, the methods of the invention involve administering to a patient in need of treatment a composition comprising a therapeutically effective amount of an IOP-lowering agent. The drug is preferably administered by pre-scleral depot administration. Other methods of administration of IOP-lowering agents include pre-tenon administration, pre-conjunctival infusion, pre-scleral depot administration, and anterior implants.

  Any agent that is capable of controlling or preventing IOP elevation would be useful in the methods of the invention, but a preferred agent is an angiogenesis inhibitor. A preferred angiogenesis inhibitor for use in the method of the present invention is 4,9 (11) -pregnadien-17α, 21-diol-3,20-dione-21-acetate, also known as anecoltab acetate, or its counterpart It is 4,9 (11) -pregnadien-17α, 21-diol-3,20-dione, also called alcohol, also known as anecoltab desacetate.

Detailed Description of Preferred Embodiments
The present invention currently addresses the treatment of IOP elevation where local injection of an IOP-lowering agent into the anterior segment of the eye, for example by near-prescleral injection of an IOP-lowering agent, is associated with glaucoma or caused by glucocorticoid administration. Based in part on the discovery that it is more effective than known therapies. In the delivery method of the present invention, the drug moves in front of the trabecular meshwork. The advantages of this method are: 1) Use of drugs that may not be effective when delivered locally, such as eye drops And 2) to achieve a sustained and long-term activity period and to avoid compliance problems.

  The present invention further allows for the long-lasting depot delivery of anecoltab acetate to allow intraocular administration of this or other relatively insoluble IOP-lowering agents by local injection of the anterior segment, particularly by injection near the anterior sclera. , Based in part on the discovery that it can provide sustained control of glaucoma-related or glucocorticoid administration to increase IOP.

  The IOP-lowering agent may be any agent that is administered to lower IOP in patients suffering from high IOP. Alternatively, the IOP-lowering agent may be a large molecule that has IOP-lowering activity but is expected to be therapeutically ineffective due to minimal corneal penetration when applied topically to the eyeball. In a preferred aspect, the IOP-lowering agent is a relatively insoluble drug and provides pre-sclera to provide control of IOP over an extended period of 1 month or more, preferably 3 months or more, most preferably 6 months or more. A drug that can be prescribed as a near depot administration. IOP lowering agents useful in the methods of the present invention include carbonic anhydrase inhibitors, alpha 1 antagonists, alpha 2 agonists, beta blockers, serotonin agonists, ethacrynic acid, miotics, or prostaglandin analogs The body is mentioned. A preferred agent for use in the methods of the present invention is an angiogenesis inhibitor, such as an angiogenesis inhibitor cortisene.

  An agent that suppresses angiogenesis is referred to in various terms, for example, as an angiogenesis inhibitor, a vascular regression agent, or an angiotropic agent. For the purposes of this specification, the term “angiogenesis inhibitor” means a compound that can be used to inhibit angiogenesis but does not have glucocorticoid activity associated with steroids. The most preferred compound for use in the method of the present invention is 4,9 (11) -pregnadien-17α, 21-diol-3,20-dione-21-acetate, also referred to as angiogenesis inhibitory cortisene, also known as anecoltab acetate. It is.

  Anecoltab acetate is cortisene and is an analog of cortisol acetate. Among the modifications to the steroid backbone are the removal of the 11-hydroxyl group, the introduction of a C9-11 double bond, and the addition of a 21-acetate group. As a result of these modifications, anecoltab acetate does not have the anti-inflammatory and immunosuppressive properties typical of glucocorticoids. Anecoltab acetate acetate down regulates trabecular meshwork myosillin expression. Using cultured trabecular cells, Clark et al. (2000) demonstrated suppression of dexamethasone-induced myosillin expression by anecoltab acetate. Clark discusses the finding that topical administration of anecoltab acetate reduces the IOP elevation associated with topical administration of dexamethasone in rabbits. However, as indicated above, many patients do not adhere to the treatment schedule prescribed for local drug use.

Examples of possible specific IOP lowering agents include beta blockers (eg, timolol, betaxolol, levobetaxolol, carteolol, levobunolol, and propanolol), carbonic anhydrase inhibitors (eg, brinsolamide, And dolzolamide), alpha-1 antagonists (eg, nipradolol), alpha-2 agonists (eg, iopidine and brimonidine), miotics (eg, pilocarpine and epinephrine), prostaglandin analogs (eg, latanoprost, travo Prost, and unoprostone), hypotensive lipids (eg, bimatoprost and compounds described in US Pat. No. 5,352,708), neuroprotective agents (eg, memantine), serotonin agonists [eg, 5- HT ₂ Agents, such as S-(+)-1- (2-aminopropyl) -indazol-6-ol], anti-angiogenic agents (e.g., anecoltab acetate), and ethacrynic acid. The ophthalmic drug may be present in the form of a pharmaceutically acceptable salt such as timolol maleate, brimonidine tartrate, or sodium diclofenac. The compounds of the invention also comprise a combination of ophthalmic drugs, for example (i) a beta blocker selected from the group consisting of betaxolol and timolol, and (ii) latanoprost, 1,5-keto latanoprost, travoprost, bimatoprost And a prostaglandin analog selected from the group consisting of unoprostone isopropyl, and (iii) a prostaglandin analog, and / or any of the other IOP-lowering agents identified above A combination of angiogenesis-inhibiting steroids (eg, anecoltab acetate) may also be included.

  In accordance with the method of the present invention, a relatively insoluble IOP-lowering composition is administered by pre-scleral depot administration to control IOP elevation associated with glaucoma or with glucoruticoid treatment. In certain embodiments of the invention, to treat an ocular back disorder, such as ocular neovascularization, edema, or diabetic retinopathy, or to treat inflammation from a surgical procedure, such as vascular closure or cataract surgery. In addition, glucocorticoids are administered intraocularly. An IOP-lowering agent, such as anecoltab acetate, is administered to the patient's eyeball by pre-scleral depot administration. The IOP-lowering agent may be administered before, simultaneously with, or after administration of the glucocorticoid. It is anticipated that administration of triamcinolone and an IOP-lowering agent can occur at intervals of minutes, hours, days, weeks, or even months.

  The IOP-lowering agents used in the methods of the invention are usually administered by pre-sclera depot administration, but alternatively the agents may be pre-tenon administration, pre-conjunctival injection, anterior implants, and May be administered in combination.

  The pre-sclera depot administration route is usually carried out as follows. The composition containing the administered IOP-lowering agent is delivered to the syringe using sterilization techniques. A 30 gauge needle is attached to the syringe. A desired amount of the composition is placed as an anterior scleral depot in the lower or lower quarter of the eyeball. See FIG. 1 for the placement of the anterior scleral depot.

  Administration of an IOP-lowering agent by pre-scleral depot administration according to the method of the present invention usually reduces IOP for a period of about 2 to 12 months, preferably about 3 to 8 months, more preferably at least 6 months. I will provide a. The amount of IOP-lowering agent in the composition delivered by pre-scleral depot administration is typically about 0.5 mL to about 1 mL, and the maximum amount of drug delivered is about 250 mg (0.5 mL delivery). ) To about 500 mg (for 1 mL delivery). Alternatively, the percentage of IOP depressant in the composition is generally up to about 50 weight percent. The determination of the maximum percentage of suspension that can be injected depends on the particle size of the IOP depressant and other factors well known to those skilled in the art.

  Similarly, formulating a composition to achieve the optimum rate necessary to achieve a therapeutic tissue level is defined by pharmacokinetics and pharmacology, and other factors well known to those skilled in the art. Is done. In general, the solubility and / or dispersibility of the drug from the particles must be greater than the rate necessary to achieve a therapeutic tissue level. As will be readily apparent to those skilled in the art, the water solubility of the drug in the suspension can be at any level, considering the following factors. 1) The minimum amount solubilized and released per day must correspond to the amount required for efficacy; 2) The injection volume must be sufficient to have the desired duration of activity; 3) Infusion limits must not be exceeded; and 4) Speeds that exceed the minimum speed necessary to meet the desired activity duration must not be compromised.

  In a preferred aspect of the present invention, anecoltab acetate is administered by pre-sclera depot administration to function more efficiently to reduce IOP elevation associated with OAG or by glucocorticoid administration. The amount of anecoltab acetate acetate administered by prescleral depot administration is generally about 1 mg to about 60 mg. Preferably, the amount of anecorb acetate acetate administered to the patient is from about 3 mg to about 30 mg, from about 12 mg to about 27 mg, or from about 21 mg to about 27 mg. The most preferred dosage is 24 mg anecoltab acetate. Alternatively, the preferred concentration of an anti-angiogenic agent in the composition administered by the method of the present invention is 0.005 to 5 weight percent.

  The compositions used in the methods of the invention are formulated according to methods known in the art depending on the particular route of administration required. The composition is typically a therapeutic amount of a relatively insoluble IOP-lowering agent, such as a large molecule that would otherwise not penetrate the cornea when delivered locally, or any known IOP-lowering agent. It is a suspension liquid containing. Such compositions are generally formulated for pre-Tenon administration, pre-conjunctival infusion, pre-scleral depot administration, anterior implants, and combinations thereof. In other embodiments, the composition may be formulated as a gel or tablet for administration as a depot or implant.

  The concentration of the IOP-lowering agent used in the methods of the present invention is routinely determined by those skilled in the art based on the type of compound, the patient, the type of composition, and other factors. Preferably, the composition has the formulation described in US Pat. Nos. 5,972,922; 5,679,666; or 5,770,592. In addition, these are each included in this specification by reference. Most preferably, the composition has the formulation described in Example 1.

  The following examples are included to demonstrate preferred embodiments of the invention. Those skilled in the art will appreciate that the techniques disclosed in the examples below represent techniques that have been discovered by the inventor to fully function in the practice of the invention, and thus the practice of the invention. It should be understood that it constitutes a preferred scheme for. However, one of ordinary skill in the art may obtain similar or similar results while carrying out many modifications in the specific embodiments disclosed without departing from the spirit and scope of the present invention. You must understand that.

Example 1
The following formulation represents a formulation suitable for use in the method of the present invention.

実施例２
約２４ｍｇの酢酸アネコルタブの単一投与を、原発性開放隅角緑内障を持つ、６名の患者の５眼に対し、その下部または下側部４分の１円のテノン下投与によって与えた。
方法：ＩＮＤおよびＩＲＢ研究者承認が得られた。患者には全てインフォームドコンセントを行った。局所麻酔下、下部ＡＪＤを与え、本発明者らは、１、２、および４週、その後は１ヶ月に１度、経過を観察した。従前の緑内障投薬は、実験期間中変えなかった。
結果：緑内障で、ＩＯＰ≧２３ｍｍＨｇ（ＰＯＡＧ［４］、ＰＤＳ［１］、ＰＸＦ［１］）を持つ６人の患者の平均年齢は５９±８歳。平均Ｃ／Ｄ比は０．８±０．２。従前の緑内障投薬は、プロスタグランジン、ベータ遮断剤、および／またはアルファ作用剤（４名は１種、１名は３種、および１名は４種）を含んでいた。処置前ＩＯＰの平均は、３１．３±１１．３ｍｍＨｇであった。６名の患者の内、５名は、３ヶ月で平均ＩＯＰが１６．４±６ｍｍＨｇで、１０．８±７．０ｍｍＨｇ（３８．５％±２１％）の平均ＩＯＰ低下であり、＞２５％のＩＯＰ低下を経験した（図２を参照されたい）。臨床的に重大な有害事象は全く見られなかった。患者は、１２ヶ月間経過観察した。ＩＯＰ低下作用は約１ヶ月でピークに達した。酢酸アネコルタブの作用の持続時間は、少なくとも１２ヶ月であった。
考察：前述の結果は、酢酸アネコルタブの前強膜近傍の配置によって得られる長期作用を実証する。２名の患者においては、強膜近傍に投与された酢酸アネコルタブが驚くべきＩＯＰ降下作用をもたらしたために、従前の緑内障投薬による治療を打ち切った。この新規治療法は、点眼薬に関連する問題、および服薬規則遵守に関する多くの論点を回避する。現在利用が可能な、いずれの補足的投薬よりもはるかに優れた、臨床的に有意義な、追加的、中期的ＩＯＰ低下を、酢酸アネコルタブの、前強膜近傍の単一デポ注入によって実現することが可能である。
実施例３
約２４ｍｇの酢酸アネコルタブの単一投与を、１回以上のグルココルチコイドの硝子体内注入誘発による緑内障を持つ、７名の患者の８眼に対し、その下部または下側部４分の１円のテノン下投与によって与えた（１つの眼あたりの注射回数は、１〜８回である）。患者は全て、緑内障に対し耐容し得る最大の投薬治療を受けており、実験期間もずっと実験前の服薬を続行した。下記の表２に示すように、治療前の平均ＩＯＰは、４０．１２５±１０．８ｍｍＨｇであった。この、酢酸アネコルタブの投与によって、２９％から５１％の範囲のＩＯＰ低下がもたらされ、ＩＯＰ低下は、有害事象もなく少なくとも６ヶ月持続し、そのため、患者の７５％において緑内障ろ過手術が回避された。

Example 2
A single dose of about 24 mg of anecoltab acetate was given to the five eyes of 6 patients with primary open-angle glaucoma by subtenon administration of the lower or lower quarter circle of Tenon.
Method: IND and IRB investigator approval was obtained. All patients received informed consent. Under local anesthesia, a lower AJD was given and we observed the course once, two, and four weeks and then once a month. Previous glaucoma medications were unchanged during the experiment.
Results: The average age of 6 patients with glaucoma and IOP ≧ 23 mmHg (POAG [4], PDS [1], PXF [1]) is 59 ± 8 years old. The average C / D ratio is 0.8 ± 0.2. Previous glaucoma medications included prostaglandins, beta-blockers, and / or alpha agonists (4 for one, one for three, and one for four). The average pre-treatment IOP was 31.3 ± 11.3 mmHg. Of the 6 patients, 5 had an average IOP of 16.4 ± 6 mmHg at 3 months and an average IOP decrease of 10.8 ± 7.0 mmHg (38.5% ± 21%),> 25% Experienced a decrease in IOP (see FIG. 2). There were no clinically significant adverse events. The patient was followed up for 12 months. The IOP lowering action peaked at about one month. The duration of action of anecoltab acetate was at least 12 months.
Discussion: The above results demonstrate the long-term effects obtained by the placement of anecoltab acetate in the vicinity of the presclera. In two patients, the previous treatment with glaucoma medication was discontinued because anecoltab acetate, administered in the vicinity of the sclera, produced a surprising IOP-lowering effect. This new treatment avoids many of the issues associated with eye drops and compliance issues. To achieve clinically significant, additional, medium-term IOP reduction, much better than any supplemental medication currently available, with a single depot injection of anecoltab acetate near the presclera Is possible.
Example 3
A single dose of about 24 mg of anecoltab acetate is applied to the lower or lower quarter quarter tenon for 8 eyes of 7 patients with glaucoma induced by intravitreal injection of one or more glucocorticoids Given by sub-administration (number of injections per eye is 1-8). All patients received the maximum medication that could be tolerated for glaucoma and continued pre-experimental medication throughout the study period. As shown in Table 2 below, the average IOP before treatment was 40.125 ± 10.8 mmHg. This administration of anecoltab acetate resulted in an IOP reduction ranging from 29% to 51%, which lasted at least 6 months without adverse events, thus avoiding glaucoma filtration surgery in 75% of patients. It was.

＊患者１は、ＩＯＰが２７ｍｍＨｇも低下したにも拘わらず、２ヶ月後実験から外された。これは、視神経萎縮陥凹がほぼ乳頭全体に達したので、彼女のＩＯＰを外科的にさらに下げることが最善であろうと判断されたためである。

* Patient 1 was removed from the experiment after 2 months despite a decrease in IOP of 27 mmHg. This is because it was determined that it would be best to surgically lower her IOP because the optic atrophy depression almost reached the entire nipple.

  In this group of 8 eyes, the 3 eyes had undergone intraocular surgery and all had received at least 3 different types of glaucoma medication (up to 6 types, 4.1 on average) Of different drug classes). IOP reduction appeared as early as one week later (mean 11.4 mmHg) and appeared to reach a maximum decline after 3 weeks (mean 16.4 mmHg). FIG. 3 shows the decrease in IOP observed in these patients over 20 months. All eyes showed significant IOP reduction.

  Despite a 45% reduction in one eye, 30 mmHg IOP after 2 months was insufficient for the patient's optic nerve, necessitating filtration surgery. In another two eyes, IOP reduction was insufficient to prevent surgical intervention. In the remaining five eyes, anecoltab acetate acetate reversed the IOP elevation by triamcinolone, prevented recurrence of the elevated IOP for up to 12 months and avoided the need for additional surgery.

Despite taking multiple glaucoma medications, average IOP reductions ranged from 29% to 51% over this 12-month period. The observed reduction in IOP was much greater than that normally observed by adding another glaucoma treatment. Furthermore, the IOP lowering effect lasted for several months.
Example 4
A carbonic anhydrase inhibitor was injected into the anterior segment of the eye of a Dutch belt rabbit with elevated IOP.
Method : IOP baseline values were measured daily for 5 days and averaged. Seven rabbits received 800 μl of non-optimized 1% ophthalmic suspension of brinzolamide (AZOPT®) subtenonally subtenonally. Seven rabbits were topically delivered with a 1% ophthalmic suspension of Brinzolamide (AZOPT®) once a day for 7 days. Seven rabbits received 800 μl of BSS® pre-Tenon capsule. Daily, IOP was monitored at 2 hours after topical instillation, and this was done for 7 days and thereafter weekly until the IOP measurement remained the same as the basal value in the two measurements.
Results : IOP did not change significantly in rabbits that received a single injection of BSS® vehicle fluid at the start of the experiment. The average pre-treatment IOP was 27.41 mmHg. The average change in IOP for this group was +0.18 mmHg. Rabbits that received daily tenon injections of brinzolamide or topical administration showed sustained IOP reduction. In the local administration group, the average value of IOP before treatment was 28.37 mmHg. The average change in IOP for this group was -2.48 mmHg. In this group, an IOP reduction of up to 11.1% from the basal value was observed during the evaluation period. In the group that received a single pre-tenon administration of 1% brinsolamide ophthalmic suspension, the mean pre-treatment IOP was 27.44 mmHg. The average change in IOP for this group was -1.85 mmHg. In the subtenon injection group, the maximum percentage of IOP reduction observed during the evaluation period was 15.9% (see FIG. 4).
Discussion : The mean percent change in IOP from baseline was statistically lower in both the locally administered and subtenon infused groups over all 7 days compared to the BSS® control in all points, Peak levels were observed within the first 3 days. Brynzolamide suspension by subtenon administration when administered at higher concentrations (eg, 5% or 10%) or encapsulated in sustained release dosage forms such as microspheres Longer lasting activity may be realized from the liquid.
Example 5
A prostaglandin analog was injected into the anterior segment of the eye of a Dutch belt rabbit with elevated IOP.
Method : Seven rabbits received 1 mL of a microsphere suspension containing 1% prostaglandin analogs under the pre-Tenon capsule. Seven rabbits received 1 mL of microsphere suspension containing 2.5% prostaglandin analogs subtenonally. Seven rabbits received an empty pre-Tenon sac administration of placebo microspheres. IOP was monitored daily for the first week, then once a week, and thereafter until IOP returned to baseline.
Results : Animals receiving 1% or 2.5% prostaglandin analog-containing microsphere suspension showed a sustained percent decrease in IOP from baseline for a minimum of 4 days. In both prostaglandin analog microsphere suspension groups, the percent change in IOP was lower than placebo microspheres at all points for 14 days. This reduction in IOP appears to be dose dependent. The 2.5% prostaglandin analog suspension administration group (average decrease in IOP = −1.97 mmHg) is more than the 1% prostaglandin analog suspension administration group (average decrease in IOP = −1.63 mmHg). Also showed a great effect. The average percent IOP reduction for the 1% suspension group ranged from 3.58% up to 8.17% over 14 days. The average percent decrease in IOP for the 2.5% suspension group ranged from 4.73% to a maximum decrease of 13.54% over the 14 day period. The placebo suspension group showed an average reduction in IOP of only 1.0 mm Hg, with a maximum percent decrease in IOP observed in placebo of only 14 days at 5.39% (see FIG. 5).
Discussion : Animals injected under tenon of empty microspheres showed a placebo effect of a mean percent change in IOP from baseline of up to 5.39%. However, when injected with a microsphere suspension loaded with a 1% or 2% concentration of a prostaglandin analog, a greater maximum percent decrease in IOP was observed (8.17% and 13.3, respectively). 54%). This dose-dependent effect lasted for a minimum of 4 days, and the residual effect of IOP reduction (percent basal value) was also observed to be slightly greater in drug-loaded microspheres compared to empty microspheres at 14 days.

  All of the compositions and / or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of the present invention have been described in connection with preferred embodiments, the compositions and / or methods described herein, and without departing from the concept, spirit, and scope of the present invention, and It will be apparent to those skilled in the art that changes may be applied in the method steps or in the sequence of steps. More specifically, it will be apparent that the agents described herein may be replaced with certain chemically and structurally related agents to achieve similar results. . All such substitutions and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

The drawings that accompany the present application briefly described below form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to these drawings in combination with the detailed description of specific embodiments presented herein.
FIG. 1 illustrates the near-scleral depot delivery method of the present invention. A suspension containing an IOP-lowering agent is administered through a pre-sclera depot administration in the lower or lower quarter of the patient's eye. FIG. 1A shows the procedure at the beginning of composition administration. FIG. 1B shows the procedure after administration of the desired amount of the composition. FIG. 2 shows the decrease in IOP over 8 months of 6 patients infused with anecoltab acetate in the anterior segment of the eye as described in Example 2. FIG. 3 shows the time course of IOP reduction in 6 patients infused with anecoltab acetate into the anterior segment of the eyeball after glucocorticoid administration, as described in Example 3. FIG. 4 shows the time course of IOP reduction in Dutch belt rabbits with elevated IOP injected with a carbonic anhydrase inhibitor into the anterior segment as described in Example 4. FIG. 5 shows the time course of IOP reduction in Dutch belt rabbits with elevated IOP injected with prostaglandin analogs in the anterior segment as described in Example 5.

Claims (18)

A method for controlling intraocular pressure in a human patient, said method comprising administering to said patient a composition comprising a therapeutically effective amount of an IOP-lowering agent, said administering under pre-Tenon administration. The method for controlling by a method selected from the group consisting of: preconjunctival injection, pre-scleral depot administration, anterior implant, and combinations thereof. 2. The method of claim 1, wherein the administration is by pre-scleral depot administration. The IOP-lowering agent is an angiogenesis inhibitor, a carbonic anhydrase inhibitor, a miotic agent, a beta blocker, an alpha 1 antagonist, an alpha 2 agonist, a serotonin agonist, ethacrynic acid, and a prostaglandin analog. The method of claim 2, wherein the method is selected from the group consisting of: The method of claim 1, wherein the IOP lowering agent comprises an angiogenesis inhibitor. The angiogenesis inhibitor comprises 4,9 (11) -pregnadien-17α, 21-diol-3,20-dione-21-acetate, and 4,9 (11) -pregnadien-17α, 21-diol-3, 5. The method of claim 4, wherein the method is selected from the group consisting of 20-diones. 6. The method of claim 5, wherein the angiogenesis inhibitor is present in the composition at a concentration of 0.005 to 5.0 weight percent. 3. The method of claim 2, wherein the IOP lowering agent comprises an angiogenesis inhibitor and the amount of the angiogenesis inhibitor administered is from about 3 mg to about 30 mg. The method according to claim 7, wherein the angiogenesis inhibitor is anecoltab acetate. 9. The method of claim 8, wherein the amount of the angiogenesis inhibitor administered is about 24 mg. The patient has or is at risk of developing intraocular pressure due to glucocorticoid administration, and the administration of the IOP-lowering agent is performed before or after the glucocorticoid administration The method of claim 1. 11. The method of claim 10, wherein the IOP lowering agent is administered after the glucocorticoid administration. 12. The method of claim 11, wherein the IOP lowering agent is administered within 1 hour after administration of the glucocorticoid. 12. The method of claim 11, wherein the angiogenesis inhibitor is administered 1 to 5 days after administration of the glucocorticoid. The method according to claim 11, wherein the angiogenesis inhibitor is administered within one week after the administration of the glucocorticoid. The method according to claim 11, wherein the angiogenesis inhibitor is administered 1 week to 8 weeks after the administration of the glucocorticoid. The method according to claim 11, wherein the angiogenesis inhibitor is administered within 3 months after the administration of the glucocorticoid. The method of claim 1, wherein the patient has primary open angle glaucoma. A composition comprising a therapeutically effective amount of an IOP-lowering agent for controlling intraocular pressure in a patient, comprising pre-tenon administration, pre-conjunctival infusion, pre-scleral depot administration, anterior implant, and combinations thereof Said composition administered by a method selected from the group consisting of:

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